The present invention relates to a method for inducing hepatic fibrosis by repeated administration of allylalcohol in animals.
Particulary, the present invention relates to the method of allylalcohol treatment in terms of dosage, frequency and duration to induce the hepatic fibrosis.
The method of the present invention establishes an animal model which is useful in the investigation of a human chronic liver disease.
Hepatic fibrosis results from chronic liver damage induced by several causes and ultimately progresses to liver cirrhosis. This is very important to understand the mechanism of hepatic fibrosis in order to find ways to prevent and cure the liver cirrhosis. Chronic liver disease including liver chirrosis and liver cancer is one of the major causes of death in Korean adults.
One single most important cause for chronic liver disease is the viral hepatitis and 7% of total Korean population is estimated to be carriers of hepatitis B virus. The most typical histological view for the chronic hepatitis caused by B virus or C virus is an inflammatory necrosis such as a periportal piecemeal necrosis. The limiting plate of the periportal liver cell is then destroyed, and the necrotic inflammation is spread to hepatic parenchyma. The portal veins are expanded, and the inflammatory legions are formed between portal veins. This necrotic inflammation is accompanied by hepatic fibrosis and progresses to liver cirrhosis (Ishak, 1994; Philips and Poucell, 1981; Ishak, 1976).
Infection of humans with hepatitis virus leads to liver necrosis. With the continuous stimuli for over 6 months, humans develop liver sclerosis through the hepatic fibrosis. It is difficult to observe humans because it takes too long to develop from hepatic fibrosis to liver sclerosis (Liaw et al., 1988; McMahon et al., 1990).
Irreversibe accumulation of collagen takes place within 20 weeks in a mouse treated with carbon tetrachloride(CCl4), and the induction period can be decreased to 8-10 weeks by pretreatment with phenobarbitol (Proctor and Chatamara, 1982). The animal model of liver sclerosis with repeated injection of carbon tetrachlodride is widely used. In this model, centrilobular necrosis is induced CCl3OO free radicals formed from .CCl3 free radicals as a result of activation by cytochrome P450 enzymes prsent in the centrilobule. The mechanism of liver sclerosis caused by carbon tetrachloride is similar to but different from that of alcoholic liver diseases and viral hepatitis (Tsukamoto et al., 1990).
Recently, Song et al suggested that the expression pattern of TGF xcex21 caused by centrilobular necrosis and periportal necrosis may be different. The animal model with induced periportal hepatic necrosis by a common bile duct ligation can develop liver sclerosis in 4 weeks, and may be useful for studying chronic viral hepatitis (Paronetto, 1966; Bhunchet and Wake, 1992; Bhunchet et al., 1996). However, the technique is highly invasive and shows a high death rate making it difficult to use.
Another model using a heterologous serum develops hepatic fibrosis by immunological pathways without the liver cell necrosis, which is different from the process of the chronic viral hepatitis (Paronetto, 1966; Bhunchet and Wake, 1992; Bhunchet et al., 1996).
Moreover, metabolic heterogeneity has been reported that the various chemical and the enzymatic activities in the liver cell as well as the microstructure of hepatic parenchyma cells depand greatly on the distribution in the hepatic lobule (Nolte and Pette, 1972; Welsh, 1972; Guger et al., 1976; Kim et al., 1977; Schmidt, 1978; Hatoff et al., 1981). Therefore, we are in need of a better animal model for human hepatic fibrosis to investigate its development to choronic disease.
Allylalcohol (CH2xe2x95x90CHCHOH) is a chemical with the molecular weight of 58.05. When injected into the intraperitoneal cavity, allylalcohol is absorbed, and oxidized to acrolein (CH2xe2x95x90CHCHO) by alcohol dehydrogenase present in the periportal liver. Acrolein is an aldehyde known to cause intense liver toxicity, specifically inducing hepatic necrosis at the periportal(Parkinson, 1996).
However, this hepatic necrosis model is not suitable for studying human chronic liver diseases. It has been necessary develop the hepatic fibrosis model similar to that accompanying human hepatic necrosis.
The present inventors use allylalcohol, known to cause the hepatic necrosis selectively at the periportal with one injection, and have developed a method to produce hepatic fibrosis in the animal model. By repeated administration of allylalcohol, these inventors were able to produce hepatic fibrosis similar to that accompanying human chronic liver disease.
It is an object of this invention to provide a method for inducing hepatic fibrosis by repeated administration of allylalcohol in animals.
It is a further object of this invention to provide the animal model which is useful for the investigation of human chronic liver disease.
Further features of the present invention will appear hereinafter.